BACKGROUND: Acquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors. METHODS: Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies. RESULTS: Twenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders. CONCLUSIONS: The combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.
BACKGROUND: Acquired resistance to antiepidermal growth factor receptor (anti-EGFR) therapy may be caused by EGFR-v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ErbB2) heterodimerization and pathway reactivation. In preclinical studies, inhibiting ErbB2 blocked this resistance mechanism and resensitized cells to anti-EGFR therapy. Cetuximab targets EGFR, whereas lapatinib inhibits both EGFR and ErbB2. The objective of this phase 1 trial was to assess the safety, dose-limiting toxicities (DLTs), and maximum tolerated doses (MTDs) of cetuximab and lapatinib in patients with solid tumors. METHODS:Patients received standard weekly cetuximab with escalating lapatinib doses of 750 mg, 1000 mg, or 1250 mg daily in 3-week cycles. DLTs were monitored through the end of cycle 2. Pretreatment and post-treatment tumor biopsies and germline DNA samples were obtained for correlative studies. RESULTS: Twenty-two patients were enrolled, and 18 patients each were evaluable for toxicity and response. Fifty-nine percent of patients had received prior anti-EGFR therapy. Common toxicities included rash and diarrhea. No patient experienced a DLT at the highest dose level, and no grade 4 toxicity was observed. Response included no complete responses, 3 partial responses, 9 patients with stable disease, and 6 patients with disease progression, for an overall response rate of 17% and a clinical benefit rate of 67%. The clinical benefit rate in patients who had previously received anti-EGFR therapy was 70%. The mean treatment duration was 4.7 cycles (range, 1-14 cycles). Decreased expression of EGFR/ErbB2 pathway components after treatment was correlated with response, whereas increased expression in the PI3K, Jak/Stat, and MAPK pathways occurred in nonresponders. CONCLUSIONS: The combination of cetuximab and lapatinib was well tolerated, had the expected toxicities, and exhibited notable clinical activity, including in patients who had received previous anti-EGFR therapy. Further clinical study of this combination is warranted.
Authors: Jonas A de Souza; Darren W Davis; Yujian Zhang; Arun Khattri; Tanguy Y Seiwert; Serdal Aktolga; Stuart J Wong; Mark F Kozloff; Sreenivasa Nattam; Mark W Lingen; Rangesh Kunnavakkam; Kerstin M Stenson; Elizabeth A Blair; Jeffrey Bozeman; Janet E Dancey; Everett E Vokes; Ezra E W Cohen Journal: Clin Cancer Res Date: 2012-02-27 Impact factor: 12.531
Authors: Tanja Schneider-Merck; Jeroen J Lammerts van Bueren; Sven Berger; Kai Rossen; Patrick H C van Berkel; Stefanie Derer; Thomas Beyer; Stefan Lohse; Wim K Bleeker; Matthias Peipp; Paul W H I Parren; Jan G J van de Winkel; Thomas Valerius; Michael Dechant Journal: J Immunol Date: 2009-11-30 Impact factor: 5.422
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Authors: Beth O Van Emburgh; Andrea Sartore-Bianchi; Federica Di Nicolantonio; Salvatore Siena; Alberto Bardelli Journal: Mol Oncol Date: 2014-05-14 Impact factor: 6.603
Authors: Filipa Lynce; Hongkun Wang; Emanuel F Petricoin; Paula R Pohlmann; Brandon Smaglo; Jimmy Hwang; Aiwu R He; Deepa S Subramaniam; John Deeken; John Marshall; Michael J Pishvaian Journal: Cancer Chemother Pharmacol Date: 2019-09-19 Impact factor: 3.333
Authors: Alexander L R Lubbock; Grant D Stewart; Fiach C O'Mahony; Alexander Laird; Peter Mullen; Marie O'Donnell; Thomas Powles; David J Harrison; Ian M Overton Journal: BMC Med Date: 2017-06-26 Impact factor: 8.775